tbuckley/cabot-search huggingface dataset:
Primary cilia support cartilage regeneration after injury
Authors: Dike Tao, Lei Zhang, Yunpeng Ding, Na Tang, Xiaoqiao Xu, Gongchen Li, Pingping Niu, Rui Yue, Xiaogang Wang, Yidong Shen, Yao Sun
Journal: International Journal of Oral Science (2023)

Abstract In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.
Beyond health-related quality of life: initial psychometric validation of a new scale for addressing the gap in assessing the full range of alopecia areata psychosocial burden
Authors: Kristina Gorbatenko-Roth, Sarah Wood, Mattea Johnson, Irmina Wallander, Jaime Nugent, Maria Hordinsky
Journal: British Journal of Dermatology (2023)

Abstract Background Patients with alopecia areata (AA) report a broad range of psychosocial outcomes beyond those assessed in existing health-related quality of life measures. Yet, to date, no psychometrically validated scale based on patient-reported outcomes (PROs) appears to exist to comprehensively measure these AA-specific psychosocial outcomes. Objectives The objective of this study was to develop such a scale, the Scale of Alopecia Areata Distress (SAAD), and to provide its initial validation evidence. Methods Using existing qualitative research on PROs for patients with AA, a pool of 144 items was generated and subsequently reviewed for relevance, redundancy, clarity and comprehensiveness by subject matter experts in AA psychosocial impacts and the research team. This review resulted in a reduced pool of 122 items, which was then administered to adult patients with AA residing in the USA. Exploratory Factor Analysis using Principal Axis Factoring extraction with oblique rotation identified the SAAD’s underlying factor structure. To reduce the SAAD item length, additional item-reduction strategies were used. Results There were 392 participants who responded to the 122 items, each with four or fewer missing item responses. Three iterations of the data analysis plan resulted in a 41-item SAAD with seven underlying factors of psychosocial impact: Emotional and Cognitive Functioning, Romantic Relationships, Family Relationships, Primary Life Responsibilities, Non-Primary Life Responsibility Activities, Stigma, and Self-Perception Change. Each factor demonstrated acceptable to high levels of internal consistency reliability. Conclusions Initial validation evidence of the SAAD-41 scale supports its potential as a comprehensive measure of AA-related psychosocial distress for US-based adults. Further scale validation is needed.
The Pregnancy-Associated Plasma Protein-A (PAPP-A) Story
Authors: Cheryl A Conover, Claus Oxvig
Journal: Endocrine Reviews (2023)

Abstract Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface–associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.
Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor
Authors: Sarath Babu Nukala, Jordan Jousma, Gege Yan, Zhenbo Han, Youjeong Kwon, Yoonje Cho, Chuyu Liu, Keith Gagnon, Sandra Pinho, Jalees Rehman, Ning-Yi Shao, Sang-Bing Ong, Won Hee Lee, Sang-Ging Ong
Journal: Cardiovascular Research (2023)

Abstract Aims Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi-receptor tyrosine kinase inhibitor, has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and results We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human-induced pluripotent stem cell-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to down-regulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirmed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and up-regulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in Has2os and degradation of the endothelial glycocalyx. Finally, we identified that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
Evaluation of the Impact of BaP Exposure on the Gut Microbiota and Allergic Responses in an OVA-Sensitized Mouse Model
Authors: Beibei Du, Xiaojun Xiao, Huailing Wang, Wenxi Li, Zhongkui Xia, Pingchang Yang, Shau-Ku Huang, Ruyi Yuan, Jie Liu, Mo Han, Yuanqiang Zou, Jiahui Zhu, Dongdong He, Jinli Lyu, Xin Jin, Xun Xu, Jian Wang, Huanming Yang, Liang Xiao, Xiaoyu Liu, Karsten Kristiansen
Journal: Environmental Health Perspectives (2023)

Background: Exposure to environmental pollutants, including benzo[a]pyrene (BaP), has been implicated in allergic diseases and intestinal microbiota homeostasis, but the environment–microbiota–immunity triangular relationship and to what extent BaP-induced remodeling of the gut microbiota contributes to intestinal allergic inflammation remain to be established. Objectives: We investigated the impact of BaP on intestinal allergic inflammation and examined the relationship between this effect and gut microbiota dysbiosis. We explored the potential ability of intestinal bacteria to degrade BaP and alleviate cytotoxicity as a detoxification strategy to counteract the effects of BaP exposure. Methods: We combined microbiome shotgun metagenomics with animal histological and intestinal allergic inflammatory responses to assess the effects of BaP (50μg/mouse per day) in a 23-d toxicity test in antigen-induced allergic female mice. In addition, genome annotation, quantitative analysis of BaP, and in vitro cytotoxicity-tests using CaCo-2 cells were conducted to infer the role of intestinal bacteria in BaP detoxification. Results: BaP exposure impacted the taxonomic composition and the functional potential of the gut microbiota and aggravated antigen-induced intestinal allergic inflammatory responses. The level of inflammatory cytokines correlated with the abundance of specific bacterial taxa, including Lachnospiraceae bacterium 28-4 and Alistipes inops. We identified 614 bacteria harboring genes implicated in the degradation of BaP, and 4 of these bacterial strains were shown to significantly reduce the cytotoxicity of BaP to CaCo-2 cells in vitro. Discussion: Using allergic female mice as a model, we investigated the relationship between BaP, microbiota, and host immune reactions, highlighting the role of gut bacteria in BaP-aggravated allergic reactions. Our findings offer novel insight toward establishing the causal relationship between BaP exposure and the occurrence of allergic disorders. Identifying gut bacteria that degrade BaP may provide new strategies for ameliorating BaP cytotoxicity. https://doi.org/10.1289/EHP11874
A standardized scoring system for conflict of interest determination and mitigation for AASLD-sponsored continuing medical education events
Authors: Stanley Martin Cohen, Joseph Ahn
Journal: Hepatology (2023)

Continuing medical education (CME) is essential to increase the knowledge, skills, and professional performance of health care providers. To keep the content of CME relevant and balanced, conflict of interest (COI) determination and mitigation is essential. While the Accreditation Council for Continuing Medical Education provides oversight and guidelines, each organization that sponsors CME programs has its own protocol for COI. To standardize and simplify the American Association for the Study of Liver Diseases' approach to COI, we propose a standardized COI disclosure scoring system for all CME programs to notify the audience of any conflicts and how such conflicts can be mitigated.
Self‐Immolated Nanoadjuvant for In Situ Vaccination Immunotherapy of Colorectal Cancer
Authors: Weiqi Wang, Qiwen Zhu, Yilan Jin, Jing Gao, Jianan Li, Xiaohua Zheng, Weidong Gao, Madiha Saeed, Weizhong Sheng, Haijun Yu
Journal: Advanced Healthcare Materials (2023)

Vaccination immunotherapy has revolutionized cancer treatment modalities. Although the immunomodulatory adjuvant generally employs for potentiating vaccine response, systemic administration may drive immune-related side effects, even immune tolerance. Therefore, tunable immunoadjuvants are highly desirable to simultaneously stimulate the immune response and mitigate systemic toxicity. Self-immolated nanoadjuvants are herein reported to potentiate vaccination immunotherapy of cancer. The nanoadjuvants are engineered by co-assembling an intracellular acidity-ionizable polymeric agonist of toll-like receptor 7/8 resiquimod (R848) and polymeric photosensitizer pyropheophorbide a (PPa). The resultant nanoadjuvants specifically accumulate at the tumor site via passive targeting and are dissociated in the acidic endosome versicles to activate PPa via protonation of the polymer backbone. Upon 671 nm laser irradiation, PPa performed photodynamic therapy to induce immunogenic cell death of tumor cells and subsequently releases R848 in a customized manner, which synergistically activates dendritic cells (DCs), promotes antigen cross-presentation, and eventually recruits cytotoxic T lymphocytes for tumor regression. Furthermore, the synergistic in situ vaccination immunotherapy with immune checkpoint blockade induce sustained immunological memory to suppress tumor recurrence in the rechallenged colorectal tumor model.
Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study
Authors: Wassim Abida, David Campbell, Akash Patnaik, Alan H. Bryce, Jeremy Shapiro, Richard M. Bambury, Jingsong Zhang, John M. Burke, Daniel Castellano, Albert Font, Vinod Ganju, Anne-Claire Hardy-Bessard, Ray McDermott, Brieuc Sautois, Dominique Spaeth, Eric Voog, Josep M. Piulats, Elias Pintus, Charles J. Ryan, Axel S. Merseburger, Gedske Daugaard, Axel Heidenreich, Karim Fizazi, Andrea Loehr, Darrin Despain, Andrew D. Simmons, Melanie Dowson, Jowell Go, Simon P. Watkins, Simon Chowdhury
Journal: European Urology (2023)
Bleeding the Excited State Energy to the Utmost: Single‐Molecule Iridium Complexes for In Vivo Dual Photodynamic and Photothermal Therapy by an Infrared Low‐Power Laser
Authors: Shi‐Jie Tang, Qing‐Fang Li, Meng‐Fan Wang, Rong Yang, Li‐Zhen Zeng, Xue‐Lian Li, Rui‐Dong Wang, Hongbin Zhang, Xiaoxia Ren, Dan Zhang, Feng Gao
Journal: Advanced Healthcare Materials (2023)

A series of cyclometalated Ir(III) complexes with morpholine and piperazine groups are designed as dual photosensitizers and photothermal agents for more efficient antitumor phototherapy via infrared low-power laser. Their ground and excited state properties, as well as the structural effect on their photophysical and biological properties, are investigated by spectroscopic, electrochemical, and quantum chemical theoretical calculations. They target mitochondria in human melanoma tumor cells and trigger apoptosis related to mitochondrial dysfunction upon irradiation. The Ir(III) complexes, particularly Ir6, demonstrate high phototherapy indexes to melanoma tumor cells and a manifest photothermal effect. Ir6, with minimal hepato-/nephrotoxicity in vitro, significantly inhibits the growth of melanoma tumors in vivo under 808 nm laser irradiation by dual photodynamic therapy and photothermal therapy and can be efficiently eliminated from the body. These results may contribute to the development of highly efficient phototherapeutic drugs for large, deeply buried solid tumors.
Drug reaction eosinophilia and systemic symptoms: Clinical phenotypic patterns according to causative drug
Authors: Kimberly G. Blumenthal, Santiago Alvarez-Arango, Daniela Kroshinsky, Ying-Chih Lo, Upeka Samarakoon, Abigail Rose Salem, Xiaoqing Fu, Fatima Bassir, Liqin Wang, Jordon Jaggers, Elizabeth Phillips, Li Zhou
Journal: Journal of the American Academy of Dermatology (2023)
Patient-Centric Approaches for Phase I Combination Trials Come on Stage
Authors: Alberto Hernando-Calvo, Elena Garralda
Journal: Cancer Discovery (2023)

Summary: A disruptive clinical trial design allowed Drilon and colleagues to demonstrate proof of concept of the potential of PF-07284892 to overcome resistance mechanisms to targeted therapies in the clinic. See related article by Drilon et al., p. 1789 (7).
A Versatile Disorder‐to‐Order Technology to Upgrade Polymers into High‐Performance Bioinspired Materials
Authors: Shengyang Liu, Shicheng He, Can Chen, Chunwang Li, Wei Luo, Kaikai Zheng, Jing Wang, Zhiyong Li, Hongyan He, Qiang Chen, Yulin Li
Journal: Advanced Healthcare Materials (2023)

Biodegradable polymer as traditional material has been widely used in the medical and tissue engineering fields, but there is a great limitation as to its inferior mechanical performance for repairing load-bearing tissues. Thus, it is highly desirable to develop a novel technology to fabricate high-performance biodegradable polymers. Herein, inspired by the bone's superstructure, a versatile disorder-to-order technology (VDOT) is proposed to manufacture a high-strength and high-elastic modulus stereo-composite self-reinforced polymer fiber. The mean tensile strength (336.1 MPa) and elastic modulus (4.1 GPa) of the self-reinforced polylactic acid (PLA) fiber are 5.2 and 2.1 times their counterparts of the traditional PLA fiber prepared by the existing spinning method. Moreover, the polymer fibers have the best ability of strength retention during degradation. Interestingly, the fiber tensile strength is even higher than those of bone (200 MPa) and some medical metals (e.g., Al and Mg). Based on all-polymeric raw materials, the VDOT endows bioinspired polymers with improved strength, elastic modulus, and degradation-controlled mechanical maintenance, making it a versatile update technology for the massive industrial production of high-performance biomedical polymers.
Clinical metagenomic sequencing of plasma microbial cell-free DNA for febrile neutropenia in patients with acute leukaemia
Authors: Sizhou Feng, Guanhua Rao, Xudong Wei, Rong Fu, Ming Hou, Yongping Song, Chunhui Xu, Peng Han, Benfa Gong, Xin Chen, Yihao Wang, Xiaoyuan Dong, Zhi Jiang, Jianxiang Wang
Journal: Clinical Microbiology and Infection (2023)
Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis
Authors: Maria Pilar Ballester, Thomas H. Tranah, Lorenz Balcar, Alessandra Fiorillo, Javier Ampuero, Annarein J.C. Kerbert, Karen L. Thomsen, María Desamparados Escudero, Mattias Mandorfer, Thomas Reiberger, Debbie L. Shawcross, Manuel Romero-Gómez, Carmina Montoliu, Juan Antonio Carbonell-Asins, Rajiv Jalan
Journal: Journal of Hepatology (2023)

Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis.
Idiopathic Pulmonary Hemosiderosis
Authors: Kazuhiro Uda, Masato Yashiro
Journal: New England Journal of Medicine (2023)

A 3-year-old girl was evaluated for fevers and a chest CT scan that showed diffuse ground-glass opacities and consolidations. The bronchoalveolar-lavage fluid was reddish-pink, and hemosiderin-laden macrophages were present.
SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Alexander Drilon, Manish R. Sharma, Melissa L. Johnson, Timothy A. Yap, Shirish Gadgeel, Dale Nepert, Gang Feng, Micaela B. Reddy, Allison S. Harney, Mohamed Elsayed, Adam W. Cook, Christina E. Wong, Ronald J. Hinklin, Yutong Jiang, Eric N. Brown, Nickolas A. Neitzel, Ellen R. Laird, Wen-I Wu, Anurag Singh, Ping Wei, Keith A. Ching, John J. Gaudino, Patrice A. Lee, Dylan P. Hartley, S. Michael Rothenberg
Journal: Cancer Discovery (2023)

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.
Safety and Efficacy of Dexpramipexole in Eosinophilic Asthma (EXHALE): A randomized controlled trial
Authors: Salman Siddiqui, Sally E. Wenzel, Michael E. Bozik, Donald G. Archibald, Steven I. Dworetzky, James L. Mather, Randall Killingsworth, Natasha Ghearing, Justin T. Schwartz, Sergei I. Ochkur, Elizabeth A. Jacobsen, William W. Busse, Reynold A. Panettieri, Calman Prussin
Journal: Journal of Allergy and Clinical Immunology (2023)

There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma.We sought to evaluate the safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma.We performed a randomized, double-blind, placebo-controlled proof-of-concept trial in adults with inadequately controlled moderate to severe asthma and blood absolute eosinophil count (AEC) greater than or equal to 300/μL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID (twice-daily) or placebo. The primary end point was the relative change in AEC from baseline to week 12. Prebronchodilator FEV1 week-12 change from baseline was a key secondary end point. Nasal eosinophil peroxidase was an exploratory end point.A total of 103 subjects were randomly assigned to dexpramipexole 37.5 mg BID (N = 22), 75 mg BID (N = 26), 150 mg BID (N = 28), or placebo (N = 27). Dexpramipexole significantly reduced placebo-corrected AEC week-12 ratio to baseline, in both the 150-mg BID (ratio, 0.23; 95% CI, 0.12-0.43; P < .0001) and the 75-mg BID (ratio, 0.34; 95% CI, 0.18-0.65; P = .0014) dose groups, corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory end point of nasal eosinophil peroxidase week-12 ratio to baseline in the 150-mg BID (median, 0.11; P = .020) and the 75-mg BID (median, 0.17; P = .021) groups. Placebo-corrected FEV1 increases were observed starting at week 4 (nonsignificant). Dexpramipexole displayed a favorable safety profile.Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand the clinical efficacy of dexpramipexole in asthma.